EP0574783A2 - Hydrogénation asymétrique - Google Patents

Hydrogénation asymétrique Download PDF

Info

Publication number: EP0574783A2
Authority: EP; European Patent Office
Prior art keywords: lower alkyl; general formula; optically active; indole; complex
Prior art date: 1992-06-19
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Granted

Application number

EP93109092A

Other languages

German (de)

English (en)

Other versions

EP0574783B1 (fr

EP0574783A3 (en

Inventor

Emil Albin Broger

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

F Hoffmann La Roche AG

Original Assignee

F Hoffmann La Roche AG

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1992-06-19

Filing date

1993-06-07

Publication date

1993-12-22

1993-06-07 Application filed by F Hoffmann La Roche AG filed Critical F Hoffmann La Roche AG

1993-12-22 Publication of EP0574783A2 publication Critical patent/EP0574783A2/fr

1994-06-08 Publication of EP0574783A3 publication Critical patent/EP0574783A3/de

1999-10-06 Application granted granted Critical

1999-10-06 Publication of EP0574783B1 publication Critical patent/EP0574783B1/fr

2013-06-07 Anticipated expiration legal-status Critical

Status Expired - Lifetime legal-status Critical Current

Links

238000009876 asymmetric hydrogenation reaction Methods 0.000 title abstract description 4
-1 nitro, amino Chemical group 0.000 claims abstract description 34
150000001875 compounds Chemical class 0.000 claims abstract description 20
238000000034 method Methods 0.000 claims abstract description 17
229910052736 halogen Inorganic materials 0.000 claims abstract description 13
238000002360 preparation method Methods 0.000 claims abstract description 12
GORXTYVHJFPOTG-UHFFFAOYSA-N 6,7-dihydropyrido[1,2-a]indol-8-ylmethanol Chemical compound C1=CC=C2N(CCC(CO)=C3)C3=CC2=C1 GORXTYVHJFPOTG-UHFFFAOYSA-N 0.000 claims abstract description 11
150000002367 halogens Chemical class 0.000 claims abstract description 11
125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 7
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
239000001257 hydrogen Substances 0.000 claims abstract description 6
125000004442 acylamino group Chemical group 0.000 claims abstract description 5
150000002431 hydrogen Chemical class 0.000 claims abstract description 5
125000000217 alkyl group Chemical group 0.000 claims description 50
239000003446 ligand Substances 0.000 claims description 28
VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 claims description 18
125000003545 alkoxy group Chemical group 0.000 claims description 14
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
150000001450 anions Chemical class 0.000 claims description 10
CHOLPKIHPFNIPE-UHFFFAOYSA-N phosphanylphosphane rhodium Chemical compound [Rh].PP CHOLPKIHPFNIPE-UHFFFAOYSA-N 0.000 claims description 9
239000002904 solvent Substances 0.000 claims description 8
125000003118 aryl group Chemical group 0.000 claims description 6
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
FTNSMTLJHGYOIV-JTQLQIEISA-N [(8s)-6,7,8,9-tetrahydropyrido[1,2-a]indol-8-yl]methanol Chemical compound C1=CC=C2N3CC[C@H](CO)CC3=CC2=C1 FTNSMTLJHGYOIV-JTQLQIEISA-N 0.000 claims description 5
125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 5
125000000129 anionic group Chemical group 0.000 claims description 4
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
150000004820 halides Chemical class 0.000 claims description 4
125000001188 haloalkyl group Chemical group 0.000 claims description 4
230000007935 neutral effect Effects 0.000 claims description 4
125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 3
ASNHGEVAWNWCRQ-UHFFFAOYSA-N 4-(hydroxymethyl)oxolane-2,3,4-triol Chemical compound OCC1(O)COC(O)C1O ASNHGEVAWNWCRQ-UHFFFAOYSA-N 0.000 claims description 3
125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
125000004414 alkyl thio group Chemical group 0.000 claims description 3
125000001072 heteroaryl group Chemical group 0.000 claims description 3
150000002825 nitriles Chemical class 0.000 claims description 3
125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 3
229910020366 ClO 4 Inorganic materials 0.000 claims description 2
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
ISWSIDIOOBJBQZ-UHFFFAOYSA-M phenolate Chemical compound [O-]C1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-M 0.000 claims description 2
229940031826 phenolate Drugs 0.000 claims description 2
125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 claims description 2
239000003054 catalyst Substances 0.000 abstract description 20
239000000543 intermediate Substances 0.000 abstract description 3
RDHJHIVIEXVZFX-UHFFFAOYSA-N phosphane;rhodium Chemical class P.P.[Rh] RDHJHIVIEXVZFX-UHFFFAOYSA-N 0.000 abstract description 2
125000006701 (C1-C7) alkyl group Chemical group 0.000 abstract 1
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
238000006243 chemical reaction Methods 0.000 description 14
239000010948 rhodium Substances 0.000 description 14
238000005984 hydrogenation reaction Methods 0.000 description 13
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
229910052703 rhodium Inorganic materials 0.000 description 11
MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 11
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 8
229910052760 oxygen Inorganic materials 0.000 description 8
239000001301 oxygen Substances 0.000 description 8
OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 7
239000011541 reaction mixture Substances 0.000 description 7
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
239000000203 mixture Substances 0.000 description 6
239000003960 organic solvent Substances 0.000 description 6
239000000725 suspension Substances 0.000 description 6
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
239000007787 solid Substances 0.000 description 5
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
239000003638 chemical reducing agent Substances 0.000 description 4
239000000460 chlorine Substances 0.000 description 4
229910052801 chlorine Inorganic materials 0.000 description 4
229910052731 fluorine Inorganic materials 0.000 description 4
239000011737 fluorine Substances 0.000 description 4
239000011521 glass Substances 0.000 description 4
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
239000000047 product Substances 0.000 description 4
150000003254 radicals Chemical class 0.000 description 4
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
WHLQQRGHOPIIMQ-UHFFFAOYSA-N [2-(2-diphenylphosphanyl-6-methylphenyl)-3-methylphenyl]-diphenylphosphane Chemical compound CC=1C=CC=C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)C=1C=1C(C)=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 WHLQQRGHOPIIMQ-UHFFFAOYSA-N 0.000 description 3
230000021736 acetylation Effects 0.000 description 3
238000006640 acetylation reaction Methods 0.000 description 3
125000001931 aliphatic group Chemical group 0.000 description 3
JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
229910052794 bromium Inorganic materials 0.000 description 3
125000004432 carbon atom Chemical group C* 0.000 description 3
VPIZGSDKJLSSKN-UHFFFAOYSA-N ethyl 6,7-dihydropyrido[1,2-a]indole-8-carboxylate Chemical compound C1=CC=C2N(CCC(C(=O)OCC)=C3)C3=CC2=C1 VPIZGSDKJLSSKN-UHFFFAOYSA-N 0.000 description 3
NPMUDAWYPUJXBK-UHFFFAOYSA-N ethyl 9-hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]indole-8-carboxylate Chemical class C1=CC=C2N3CCC(C(=O)OCC)C(O)C3=CC2=C1 NPMUDAWYPUJXBK-UHFFFAOYSA-N 0.000 description 3
238000001704 evaporation Methods 0.000 description 3
239000000706 filtrate Substances 0.000 description 3
125000005843 halogen group Chemical group 0.000 description 3
229910052740 iodine Inorganic materials 0.000 description 3
229910052744 lithium Inorganic materials 0.000 description 3
239000012074 organic phase Substances 0.000 description 3
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
238000010992 reflux Methods 0.000 description 3
239000000741 silica gel Substances 0.000 description 3
229910002027 silica gel Inorganic materials 0.000 description 3
239000007858 starting material Substances 0.000 description 3
238000003756 stirring Methods 0.000 description 3
239000000758 substrate Substances 0.000 description 3
KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 2
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
PRBHEGAFLDMLAL-UHFFFAOYSA-N 1,5-Hexadiene Natural products CC=CCC=C PRBHEGAFLDMLAL-UHFFFAOYSA-N 0.000 description 2
OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
LINDOXZENKYESA-UHFFFAOYSA-N TMG Natural products CNC(N)=NC LINDOXZENKYESA-UHFFFAOYSA-N 0.000 description 2
FTNSMTLJHGYOIV-SNVBAGLBSA-N [(8r)-6,7,8,9-tetrahydropyrido[1,2-a]indol-8-yl]methanol Chemical compound C1=CC=C2N3CC[C@@H](CO)CC3=CC2=C1 FTNSMTLJHGYOIV-SNVBAGLBSA-N 0.000 description 2
VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
239000013078 crystal Substances 0.000 description 2
150000004292 cyclic ethers Chemical class 0.000 description 2
ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 2
238000001035 drying Methods 0.000 description 2
238000003379 elimination reaction Methods 0.000 description 2
150000002148 esters Chemical class 0.000 description 2
PYGSKMBEVAICCR-UHFFFAOYSA-N hexa-1,5-diene Chemical compound C=CCCC=C PYGSKMBEVAICCR-UHFFFAOYSA-N 0.000 description 2
239000011630 iodine Substances 0.000 description 2
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
239000012299 nitrogen atmosphere Substances 0.000 description 2
SJYNFBVQFBRSIB-UHFFFAOYSA-N norbornadiene Chemical compound C1=CC2C=CC1C2 SJYNFBVQFBRSIB-UHFFFAOYSA-N 0.000 description 2
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
239000011780 sodium chloride Substances 0.000 description 2
125000001424 substituent group Chemical group 0.000 description 2
LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
238000004809 thin layer chromatography Methods 0.000 description 2
238000005406 washing Methods 0.000 description 2
PAXWODJTHKJQDZ-VHSXEESVSA-N (1r,4s)-1,7,7-trimethyl-2-oxo-3-oxabicyclo[2.2.1]heptane-4-carbonyl chloride Chemical compound C1C[C@]2(C(Cl)=O)OC(=O)[C@@]1(C)C2(C)C PAXWODJTHKJQDZ-VHSXEESVSA-N 0.000 description 1
VYXHVRARDIDEHS-QGTKBVGQSA-N (1z,5z)-cycloocta-1,5-diene Chemical compound C\1C\C=C/CC\C=C/1 VYXHVRARDIDEHS-QGTKBVGQSA-N 0.000 description 1
LYXHWHHENVLYCN-QMDOQEJBSA-N (1z,5z)-cycloocta-1,5-diene;rhodium;tetrafluoroborate Chemical compound [Rh].F[B-](F)(F)F.C\1C\C=C/CC\C=C/1.C\1C\C=C/CC\C=C/1 LYXHWHHENVLYCN-QMDOQEJBSA-N 0.000 description 1
PGLASKORVDVZEZ-UHFFFAOYSA-N (2z)-1-cycloundecyl-2-diazocycloundecane Chemical compound [N-]=[N+]=C1CCCCCCCCCC1C1CCCCCCCCCC1 PGLASKORVDVZEZ-UHFFFAOYSA-N 0.000 description 1
DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 description 1
239000004912 1,5-cyclooctadiene Substances 0.000 description 1
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
HSPRASOZRZDELU-LMOVPXPDSA-N 3-[(8s)-8-[(dimethylamino)methyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methylindol-3-yl)pyrrole-2,5-dione;hydrochloride Chemical compound Cl.C12=CC=CC=C2N2CC[C@H](CN(C)C)CC2=C1C1=C(C=2C3=CC=CC=C3N(C)C=2)C(=O)NC1=O HSPRASOZRZDELU-LMOVPXPDSA-N 0.000 description 1
CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
208000027775 Bronchopulmonary disease Diseases 0.000 description 1
208000024172 Cardiovascular disease Diseases 0.000 description 1
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
239000012448 Lithium borohydride Substances 0.000 description 1
HBBGRARXTFLTSG-UHFFFAOYSA-N Lithium ion Chemical compound [Li+] HBBGRARXTFLTSG-UHFFFAOYSA-N 0.000 description 1
JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical class O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 1
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
KRJVQCZJJSUHHO-UHFFFAOYSA-N [2-(2-diphenylphosphanyl-6-methoxyphenyl)-3-methoxyphenyl]-diphenylphosphane Chemical compound COC=1C=CC=C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)C=1C=1C(OC)=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 KRJVQCZJJSUHHO-UHFFFAOYSA-N 0.000 description 1
WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
239000012346 acetyl chloride Substances 0.000 description 1
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
239000004480 active ingredient Substances 0.000 description 1
239000008186 active pharmaceutical agent Substances 0.000 description 1
125000002252 acyl group Chemical group 0.000 description 1
125000004849 alkoxymethyl group Chemical group 0.000 description 1
125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
238000004458 analytical method Methods 0.000 description 1
HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
239000003125 aqueous solvent Substances 0.000 description 1
239000012298 atmosphere Substances 0.000 description 1
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
230000015572 biosynthetic process Effects 0.000 description 1
235000010290 biphenyl Nutrition 0.000 description 1
239000004305 biphenyl Substances 0.000 description 1
229940006460 bromide ion Drugs 0.000 description 1
125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
238000003965 capillary gas chromatography Methods 0.000 description 1
230000003197 catalytic effect Effects 0.000 description 1
229910001914 chlorine tetroxide Inorganic materials 0.000 description 1
125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
150000001993 dienes Chemical class 0.000 description 1
SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
201000010099 disease Diseases 0.000 description 1
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
230000008030 elimination Effects 0.000 description 1
125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
GULUEXMQSOHENG-UHFFFAOYSA-N ethyl 9-acetyloxy-6,7,8,9-tetrahydropyrido[1,2-a]indole-8-carboxylate Chemical compound C1=CC=C2N3CCC(C(=O)OCC)C(OC(C)=O)C3=CC2=C1 GULUEXMQSOHENG-UHFFFAOYSA-N 0.000 description 1
YQZUGFCCFIEUIN-UHFFFAOYSA-N ethyl 9-hydroxy-6,7-dihydropyrido[1,2-a]indole-8-carboxylate Chemical compound C1=CC=C2N(CCC(C(=O)OCC)=C3O)C3=CC2=C1 YQZUGFCCFIEUIN-UHFFFAOYSA-N 0.000 description 1
230000008020 evaporation Effects 0.000 description 1
125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
238000004817 gas chromatography Methods 0.000 description 1
229910000856 hastalloy Inorganic materials 0.000 description 1
230000001900 immune effect Effects 0.000 description 1
238000011065 in-situ storage Methods 0.000 description 1
239000011261 inert gas Substances 0.000 description 1
230000002757 inflammatory effect Effects 0.000 description 1
150000002500 ions Chemical class 0.000 description 1
150000002641 lithium Chemical group 0.000 description 1
229910001416 lithium ion Inorganic materials 0.000 description 1
UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
238000004519 manufacturing process Methods 0.000 description 1
239000012452 mother liquor Substances 0.000 description 1
125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
125000001624 naphthyl group Chemical group 0.000 description 1
125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
229910052757 nitrogen Inorganic materials 0.000 description 1
230000000771 oncological effect Effects 0.000 description 1
230000003287 optical effect Effects 0.000 description 1
125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
125000005062 perfluorophenyl group Chemical group FC1=C(C(=C(C(=C1F)F)F)F)* 0.000 description 1
125000004437 phosphorous atom Chemical group 0.000 description 1
229910052698 phosphorus Inorganic materials 0.000 description 1
239000011591 potassium Substances 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
238000011321 prophylaxis Methods 0.000 description 1
125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
125000006239 protecting group Chemical group 0.000 description 1
239000000376 reactant Substances 0.000 description 1
230000002829 reductive effect Effects 0.000 description 1
150000003283 rhodium Chemical class 0.000 description 1
LCAWZYUJRNVLIG-UHFFFAOYSA-K rhodium(3+);triperchlorate Chemical compound [Rh+3].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O LCAWZYUJRNVLIG-UHFFFAOYSA-K 0.000 description 1
239000002002 slurry Substances 0.000 description 1
229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
235000017557 sodium bicarbonate Nutrition 0.000 description 1
239000012279 sodium borohydride Substances 0.000 description 1
229910000033 sodium borohydride Inorganic materials 0.000 description 1
229910052717 sulfur Inorganic materials 0.000 description 1
239000011593 sulfur Substances 0.000 description 1
GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
238000003786 synthesis reaction Methods 0.000 description 1
JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
238000011282 treatment Methods 0.000 description 1
125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems

Definitions

acyl from the group “acylamino” denotes a group which is derived from an alkane carboxylic acid having up to 7, preferably up to 4, carbon atoms, such as, for example, formyl, acetyl, propionyl or butyryl, or from an aromatic carboxylic acid, e.g. B. benzoyl.
the coordinating anionic ligands (X) and optically active atropisomeric diphosphine ligands (Y) are in particular the ligands specified in the following definition of the formulas III 'and IV'.
the anion A- is also explained in more detail there.
An optically active rhodium-diphosphine complex of the general formula is preferably used as the catalyst for the process according to the invention
p in the formula VI is a number 1 to 3
the two or two of the radicals R 12 are preferably in the 5,5 'position.
This compound is a valuable intermediate in the synthesis of (S) -3- ⁇ 6,7,8,9-tetrahydro-8 - [(dimethylamino) methyl] pyrido [1,2-a] indol-10-yl ⁇ - 4- (1-methyl-3-indolyl) -1H-pyrrole-2,5-dione hydrochloride, a valuable pharmaceutical active ingredient for the treatment or prophylaxis of diseases, especially inflammatory, immunological, oncological, bronchopulmonary and cardiovascular diseases.
the mother liquor is filtered through a layer of 5 g of silica gel. Wash with 100 ml of diethyl ether and evaporation of the combined filtrate provide an additional 2.44 g (10.7%) of product; GC 100 area%; 97.7% ee

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Catalysts (AREA)
Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

EP93109092A 1992-06-19 1993-06-07 Hydrogénation asymétrique Expired - Lifetime EP0574783B1 (fr)

Applications Claiming Priority (6)

Application Number	Priority Date	Filing Date	Title
CH194492		1992-06-19
CH194492		1992-06-19
CH1944/92		1992-06-19
CH826/93		1993-03-18
CH82693		1993-03-18
CH82693		1993-03-18

Publications (3)

Publication Number	Publication Date
EP0574783A2 true EP0574783A2 (fr)	1993-12-22
EP0574783A3 EP0574783A3 (en)	1994-06-08
EP0574783B1 EP0574783B1 (fr)	1999-10-06

Family

ID=25685815

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
EP93109092A Expired - Lifetime EP0574783B1 (fr)	1992-06-19	1993-06-07	Hydrogénation asymétrique

Country Status (7)

Country	Link
US (1)	US5374727A (fr)
EP (1)	EP0574783B1 (fr)
JP (1)	JP2788841B2 (fr)
AT (1)	ATE185346T1 (fr)
DE (1)	DE59309812D1 (fr)
DK (1)	DK0574783T3 (fr)
ES (1)	ES2138605T3 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
EP0691325A1 (fr)	1994-07-07	1996-01-10	F. Hoffmann-La Roche Ag	Hydrogénation asymmétrique de dérivés de la cétoisophorone
CN104854069A (zh) *	2012-12-18	2015-08-19	帝斯曼知识产权资产管理有限公司	由6,10-二甲基十一碳-5-烯-2-酮或6,10-二甲基十一碳-5,9-二烯-2-酮制备的(6r,10r)-6,10,14-三甲基十五烷-2-酮
CN104854070A (zh) *	2012-12-18	2015-08-19	帝斯曼知识产权资产管理有限公司	由(r)-3,7-二甲基辛-6-烯醛制备的(6r,10r)-6,10,14-三甲基十五烷-2-酮
CN110229152A (zh) *	2019-06-14	2019-09-13	中国药科大学	一种2-位双取代吲哚啉-3-酮类化合物及其不对称合成方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
DE19532320A1 (de) *	1995-09-01	1997-03-06	Bayer Ag	Verfahren zur Herstellung von optisch aktiven ortho-substituierten 4-Aryl-Dihydropyridinen

Citations (2)

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Publication number	Priority date	Publication date	Assignee	Title
EP0158875A2 (fr) *	1984-04-19	1985-10-23	F. Hoffmann-La Roche Ag	Rhodium-diphosphine complexes chirales pour des hydrogénatiens asymmétriques
EP0540956A1 (fr) *	1991-11-04	1993-05-12	F. Hoffmann-La Roche Ag	Procédé de fabrication de maléimides substitués

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US4155247A (en) *	1977-05-02	1979-05-22	Westinghouse Electric Corp.	Multi-part gas sampler
DE3018388A1 (de) *	1980-05-14	1981-11-19	Basf Ag, 6700 Ludwigshafen	Verfahren zur herstellung von optisch aktiven verbindungen und deren verwendung zur herstellung von vitamin e
DK350383A (da) *	1982-08-27	1984-02-28	Hoffmann La Roche	Phosphorforbindelser
US4962242A (en) *	1986-08-27	1990-10-09	Takasago Perfumery Co., Ltd.	Process for producing optically active alcohols
EP0398132B1 (fr) *	1989-05-18	1995-09-20	F. Hoffmann-La Roche Ag	Composés du phosphore
CZ280199B6 (cs) *	1990-12-21	1995-11-15	Novartis Ag	Asymetrická hydrogenace

1993
- 1993-05-27 US US08/068,358 patent/US5374727A/en not_active Expired - Fee Related
- 1993-06-07 ES ES93109092T patent/ES2138605T3/es not_active Expired - Lifetime
- 1993-06-07 DK DK93109092T patent/DK0574783T3/da not_active Application Discontinuation
- 1993-06-07 AT AT93109092T patent/ATE185346T1/de not_active IP Right Cessation
- 1993-06-07 DE DE59309812T patent/DE59309812D1/de not_active Expired - Fee Related
- 1993-06-07 EP EP93109092A patent/EP0574783B1/fr not_active Expired - Lifetime
- 1993-06-16 JP JP5168371A patent/JP2788841B2/ja not_active Expired - Fee Related

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
EP0158875A2 (fr) *	1984-04-19	1985-10-23	F. Hoffmann-La Roche Ag	Rhodium-diphosphine complexes chirales pour des hydrogénatiens asymmétriques
EP0540956A1 (fr) *	1991-11-04	1993-05-12	F. Hoffmann-La Roche Ag	Procédé de fabrication de maléimides substitués

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Title
TETRAHEDRON Bd. 47, Nr. 26 , 24. Juni 1991 , OXFORD GB Seiten 4645 - 4664 RINO A. BIT ET AL 'A Dieckmann/ring expansion approach to tetrahydropyrido- and tetrahydroazepino-[1,2-aÜindoles' *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
EP0691325A1 (fr)	1994-07-07	1996-01-10	F. Hoffmann-La Roche Ag	Hydrogénation asymmétrique de dérivés de la cétoisophorone
CN104854069A (zh) *	2012-12-18	2015-08-19	帝斯曼知识产权资产管理有限公司	由6,10-二甲基十一碳-5-烯-2-酮或6,10-二甲基十一碳-5,9-二烯-2-酮制备的(6r,10r)-6,10,14-三甲基十五烷-2-酮
CN104854070A (zh) *	2012-12-18	2015-08-19	帝斯曼知识产权资产管理有限公司	由(r)-3,7-二甲基辛-6-烯醛制备的(6r,10r)-6,10,14-三甲基十五烷-2-酮
CN110229152A (zh) *	2019-06-14	2019-09-13	中国药科大学	一种2-位双取代吲哚啉-3-酮类化合物及其不对称合成方法
CN110229152B (zh) *	2019-06-14	2020-06-23	中国药科大学	一种2-位双取代吲哚啉-3-酮类化合物及其不对称合成方法

Also Published As

Publication number	Publication date
ES2138605T3 (es)	2000-01-16
ATE185346T1 (de)	1999-10-15
JPH0665240A (ja)	1994-03-08
JP2788841B2 (ja)	1998-08-20
DK0574783T3 (da)	2000-03-13
EP0574783B1 (fr)	1999-10-06
EP0574783A3 (en)	1994-06-08
US5374727A (en)	1994-12-20
DE59309812D1 (de)	1999-11-11

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